Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was performed to determine the influence of pharmaceutical intervention on parameters of blood coagulation and fibrinolysis in hypercholesterolemic patients. Eighteen otherwise-healthy individuals with heterozygous familial hypercholesterolemia were treated with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (simvastatin, 40 mg daily) for 12-14 weeks followed by additional treatment with omega-3 fatty acids (equivalent to 4 g eicosapentaenoic acid/docosahexaenoic acid daily) for 6 more weeks. With simvastatin treatment, the mean decreases in total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B (apo B) were 39%, 46%, and 36%, respectively. Only minor changes in high density lipoprotein (HDL) cholesterol and apo A-1 were recorded. omega-3 fatty acids had minor additional effects. The most prominent effects on the blood coagulation system were the changes in extrinsic pathway inhibitor (EPI), which is the inhibitor of the factor VIIa-tissue thromboplastin complex. EPI activity decreased from a median of 153% to 111% (p less than 0.001) with simvastatin treatment and to 112% (p less than 0.001) on the combined regimen. EPI activity was significantly correlated with LDL cholesterol (r = 0.78), total cholesterol (r = 0.77), apo B (r = 0.65), and apo A-1 (r = 0.45). Multiple stepwise regression analysis showed that LDL cholesterol was the most important predictor of EPI activity, which suggests that a majority of EPI activity in plasma is associated with LDL. Moreover, the alteration in EPI activity was correlated closely with the corresponding alteration in LDL, which suggests a direct relation between a coagulation-inhibitor activity and a pharmaceutical lipid-related response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system. 198 91

Sulphatide is found to be a major glycosphingolipid in serum lipoproteins of rabbit and its content is markedly elevated in serum of WHHL rabbit, an animal model for human familial hypercholesterolemia. On analysis of tissue sulphatide contents, serum appears to derive its sulphatide from liver (90%) and small intestine (10%) and passes on to aorta of WHHL rabbit which is found to have a large amount of sulphatide while none is found in normal aorta. Thus it seems that sulphatide finally accumulates in arterial walls along with the progression of atherosclerosis in WHHL rabbit. Since sulphatide at median concentration (8 nmole/ml serum) in various mammals is found to increase activated partial thromboplastin time by 25%, it is suggested that anticoagulant activity may be one of the physiological functions of sulphatide in serum. The observation of an increase in activated partial thromboplastin time by 2.5-fold on injection of sulphatide (10 mg/kg body wt) into rabbit suggests that sulphatide may be an effective and safe antithrombotic agent.
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PMID:Sulphatide as a major glycosphingolipid in WHHL rabbit serum lipoproteins and its anticoagulant activity. 800 18

The very rapid clearance of human recombinant tissue factor pathway inhibitor (h-rTFPI) may result from its binding to vascular proteogly can and LDL receptor-related protein (LRP). To investigate the effect of factor Xa on the clearance of h-rTFPI, we developed a specific ELISA for h-rTFPI/factor Xa complex, and compared the pharmacokinetic parameters of h-rTFPI/factor Xa complex and the clearance rate of the cellular proteogly can-associated h-rTFPI/factor Xa complex with those of h-rTFPI by itself in rabbits. We found that the h-rTFPI/factor Xa complex disappeared from circulation at a rapid rate of clearance, having pharmacokinetic parameters similar to those of non-complexed h-rTFPI. After the rapid disappearance of the h-rTFPI complex from plasma, an intravenous injection of heparin resulted in a release of h-rTFPI/factor Xa complex into plasma. However, the recovery of heparin-releasable h-rTFPI/factor Xa decreased significantly in a time-dependent manner. Therefore, we examined the half-life of proteogly can-associated h-rTFPI/factor Xa and determined it to be 51 min, which was significantly shorter than that of h-rTFPI by itself (107 min). These results suggest that a complex formation of h-rTFPI with factor Xa promotes a clearance of proteogly can-associated h-rTFPI existing in the liver and kidney.
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PMID:The clearance of proteoglycan-associated human recombinant tissue factor pathway inhibitor (h-rTFPI) in rabbits: a complex formation of h-rTFPI with factor Xa promotes a clearance rate of h-rTFPI. 883 15

We performed an intraindividual comparison of the effect on the coagulation system of two selective apheresis procedures: Direct Adsorption of Lipoproteins (DALI) and Heparin-induced Lipoprotein Fibrinogen Precipitation (HELP). Six patients suffering from heterozygous familial hypercholesterolemia have been treated with 2 sessions of each procedure. Anticoagulation was carried out according to usual recommendations. Blood samples were taken before, immediately after and on the second day after the sessions. We assessed global coagulation tests (prothrombin time, activated partial thromboplastin time), fibrinogen, prothrombin fragment F 1 + 2 and a variety of factors (Factors II, V, VII, XIII, IX, X, XI, XII, XIIa; von Willebrand Factor; collagen-binding activity, prekallikrein, high-molecular weight kininogen) and antagonists (antithrombin III, protein S activity, free protein S). In fact, all parameters measured have been influenced by the apheresis treatment. Fibrinogen is lowered more by HELP which also has a more definite impact on factors belonging to the prothrombin complex (II, VII, X). In contrast, the major effects of the DALI system have been seen on the intrinsic pathway of the coagulation system (IX, XI, prekallikrein, high-molecular-weight kininogen). With both systems, no increases in activated Factor XII or in prothrombin fragment F 1 + 2 have been observed. These data provide a solid basis for individual adaptations of anticoagulant doses.
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PMID:Intraindividual comparison of the impact of two selective apheresis methods (DALI and HELP) on the coagulation system. 1079 65

Mipomersen is a second-generation antisense oligonucleotide indicated as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH). Warfarin is commonly prescribed for a variety of cardiac disorders in homozygous familial hypercholesterolemia population, and concurrent use of warfarin and mipomersen is likely. This open-label, single-sequence 2-period phase 1 study in healthy subjects evaluated the potential drug-drug interactions between mipomersen and warfarin. The subjects received a single oral 25 mg dose of warfarin alone on day 1, and after a 7-day washout period, received 200 mg mipomersen alone subcutaneously every other day on days 8-12, and received both concurrently on day 14. Coadministration of mipomersen did not change the pharmacodynamics (international normalized ratio, prothrombin time, and activated partial thromboplastin time) and pharmacokinetics (PK) of warfarin. There were no clinically significant changes in the PK of mipomersen with concurrent administration of warfarin. There were no events indicative of an increase in bleeding tendency when warfarin was coadministered with mipomersen, and the adverse event profile of mipomersen did not appear to be altered in combination with warfarin, as compared with that of the respective reference treatment. The combination of these 2 medications appeared to be safe and well tolerated. These results suggest that the dosage adjustment of warfarin or mipomersen is not expected to be necessary with coadministration.
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PMID:Lack of clinical pharmacodynamic and pharmacokinetic drug-drug interactions between warfarin and the antisense oligonucleotide mipomersen. 2469 Dec 75